Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.
Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.
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DOI：
10.1371/journal.pgen.1003751
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Paracchini S
中科院分区：
文献类型：
--
作者：
Brandler WM;Morris AP;Evans DM;Scerri TS;Kemp JP;Timpson NJ;St Pourcain B;Smith GD;Ring SM;Stein J;Monaco AP;Talcott JB;Fisher SE;Webber C;Paracchini S
人类在大脑组织中表现出结构和功能的不对称，尤其是在语言和惯用手方面。这些不对称性的分子基础尚不清楚。我们报告了一项全基因组关联研究的荟萃分析，对阅读障碍[阅读障碍(RD)]个体的相对手技能的定量测量进行了荟萃分析(n = 728)。最强关联的突变体rs7182874(P = 8.68×10−9)位于PCSK6，进一步支持了我们先前报道的关联。我们还证实了这种关联在RD个体中的特异性；在一般人群队列中，相同的基因座与相对的手部技能无关(n = 2,666)。由于已知PCSK6在小鼠左/右(LR)不对称的发展中调节节点，我们开发了一种新的GWAS途径分析方法，使用基因集浓缩来测试在其在小鼠中的破坏导致LR不对称表型的基因的同源基因中高关联变量的过度表达。在15个LR不对称表型中，有4个表现为过度表达(FDR≤为5%)。我们在普通人群队列中复制了这些表型中的三种：内翻、异位和右室双出口(≤为5%)。我们的发现引导我们提出，利手是一个多基因特征，部分由在发育早期建立LR身体不对称性的分子机制控制。人类已经形成了一种群体层面的偏见，倾向于使用工具时用右手。了解利手的遗传基础有助于解释为什么存在这种偏见，并可能为利手和大脑不对称的进化提供线索。我们在一组阅读障碍患者中测试了相对手部技能和数十万种遗传变异之间的相关性。最强的相关变异是在PCSK6基因中，这是一种将节裂解成活性形式的酶。在从蜗牛到哺乳动物的不同物种中，Node在建立左/右不对称(LR)的过程中起着关键作用。PCSK6基因敲除小鼠表现出LR不对称缺陷，如异位(器官位置异常)。我们在人类版本的基因中发现了与相对手艺相关的进一步变异，这些变异也会导致小鼠的LR不对称表型异质性和部位反转(器官不对称的逆转)。这些结果在没有阅读障碍的独立普通人群队列中重复出现。我们认为，利手受许多变异的控制，其中一些变异也在决定身体LR不对称性的基因中。
Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68×10−9), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR≤5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR≤5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development. Humans have developed a population level bias towards right-handedness for tool-use. Understanding the genetic basis of handedness can help explain why this bias exists and may offer clues into the evolution of handedness and brain asymmetry. We have tested for correlation between relative hand skill and hundreds of thousands of genetic variants in a cohort of individuals with reading disability. The strongest associated variant is in the gene PCSK6, an enzyme that cleaves NODAL into an active form. NODAL plays a key role during the establishment of left/right (LR) asymmetry in diverse species, from snails to mammals. Pcsk6 knock-out mice display LR asymmetry defects like heterotaxia (abnormal organ positioning). We uncovered further variants associated with relative hand skill in the human versions of genes that also cause the LR asymmetry phenotypes heterotaxia, and situs inversus (reversal of organ asymmetry) when knocked out in mice. These results replicate in an independent general population cohort without reading disability. We propose that handedness is under the control of many variants, some of which are in genes that also contribute to the determination of body LR asymmetry.
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影响因子：
9.2
作者：
Barth, KA;Miklosi, A;Watkins, J;Bianco, IH;Wilson, SW;Andrew, RJ
通讯作者：
Andrew, RJ
影响因子：
14.9
作者：
Blake JA;Bult CJ;Eppig JT;Kadin JA;Richardson JE;Mouse Genome Database Group
通讯作者：
Mouse Genome Database Group
影响因子：
4.5
作者：
Benadiba C;Magnani D;Niquille M;Morlé L;Valloton D;Nawabi H;Ait-Lounis A;Otsmane B;Reith W;Theil T;Hornung JP;Lebrand C;Durand B
通讯作者：
Durand B
DOI：
10.1073/pnas.94.25.14015
发表时间：
1997-12-09
影响因子：
11.1
作者：
Dassonville, P;Zhu, XH;Ashe, J
通讯作者：
Ashe, J
影响因子：
3.7
作者：
Arning, Larissa;Ocklenburg, Sebastian;Beste, Christian
通讯作者：
Beste, Christian